Efficient synthesis of phenanthridinone derivatives via a palladium-catalyzed coupling process

Article abstract of DOI:10.1021/ol062599z

(Chemical Equation Presented) A palladium-mediated domino reaction was developed to conveniently synthesize phenanthridinone derivatives. Phosphine ligand 1 strongly promotes the domino process, which includes aryl-aryl coupling and C-N bond formations concomitant with a deamidation reaction. The versatility and applicability to a broad range of substrates make this reaction useful for the development of bioactive derivatives.

Full text of DOI:10.1021/ol062599z

ORGANIC
LETTERS
2007
Vol. 9, No. 2
183-186
Efficient Synthesis of Phenanthridinone
Derivatives via a Palladium-Catalyzed
Coupling Process†
Takumi Furuta,* Yuki Kitamura, Ayano Hashimoto, Satoshi Fujii,
Kiyoshi Tanaka, and Toshiyuki Kan*
School of Pharmaceutical Sciences, UniVersity of Shizuoka, 52-1 Yada,
Suruga-ku, Shizuoka 422-8526, Japan
furuta@u-shizuoka-ken.ac.jp; kant@u-shizuoka-ken.ac.jp
Received October 22, 2006
ABSTRACT
A palladium-mediated domino reaction was developed to conveniently synthesize phenanthridinone derivatives. Phosphine ligand 1 strongly
promotes the domino process, which includes aryl aryl coupling and C N bond formations concomitant with a deamidation reaction. The
versatility and applicability to a broad range of substrates make this reaction useful for the development of bioactive derivatives.
−
−
Palladium-mediated reactions are powerful synthetic tools
for constructing highly complex molecules. Among these
reactions, C-N bond formations1 have been recently em-
ployed as the key step for the total synthesis of nitrogen-
containing natural products as well as for the construction
of heterocycles in drug discovery due to their high efficiency
and compatibility with numerous functional groups.
reactions by virtue of ligands 1 and 2, we have explored
â-lactam formation from 2-bromobenzamide derivative 7.
Initially, we expected that five-membered palladacycle 8,
which is readily afforded by oxidative addition of Pd(0),
would yield desired product 9 via a reductive elimination of
Pd(II) species (Scheme 1). However, the reaction unexpect-
edly afforded phenanthridinone derivative 10 as the sole
We have recently developed novel phenylnaphthyl phos-
phine ligands 1 and 2 and have demonstrated their excellent
functions in Pd-catalyzed intramolecular amidations.2 Utiliz-
ing 1 and 2, we have efficiently prepared indoline 5 and
quinoline derivative 6 from 3 and 4, respectively. As part of
our continuing investigation on these C-N bond forming
Scheme 1. Pd-Mediated Lactam Ring Formations Using
Ligand 1
† This paper is dedicated to the memory of the late Prof. Kiyoshi Tanaka,
who passed away December 8, 2004.
(1) For reviews on Pd-catalyzed C-N bond formations, see: (a) Wolfe,
J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998,
31, 805-818. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-
2067. (c) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576,
125-146. (d) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B.
Tetrahedron 2002, 58, 2041-2075.
(2) (a) Yoshikawa, S.; Odaira, J.; Kitamura, Y.; Bedekar, A. V.; Furuta,
T.; Tanaka, K. Tetrahedron 2004, 60, 2225-2234. (b) Kitamura, Y.;
Hashimoto, A.; Yoshikawa, S.; Odaira, J.; Furuta, T.; Kan, T.; Tanaka, K.
Synlett 2006, 115-117.
10.1021/ol062599z CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/16/2006

product by a homocoupling reaction of 7. This coupling
reaction should proceed through a domino process concomi-
tant with C-C and C-N bond forming reactions.
Table 2. Effects of the Amide Substituentsa
Because we are interested in ligand efficacy and because
of the importance of phenanthridinone derivatives,3 we
further investigated this reaction. Herein, we report the details
of this domino reaction in the presence of ligand 1.
First, we explored the appropriate synthetic conditions with
11 (Table 1).4 Ligand 1 afforded 12 in an excellent yield of
entry
substrate
13a: R ) Me
13b: R ) allyl
13c: R ) Ph
13d: R ) p-methoxybenzyl
13e: R ) 2,4-dimethoxybenzyl
product
yield (%)b
1
2
3
4
5
14a
14b
14c
14d
14e
28
32
23
64
72
Table 1. Ligand Effect on the Coupling Reaction of 11a
a The reaction was conducted with Pd(OAc)2 (6.0 mol %), ligand 1 (5.0
mol %), and Cs2CO3 (1.0 equiv) in dioxane for 24 h at 100 °C. bYields of
the isolated products.
entry
catalyst
yield (%)b
corresponding products 14d and 14e in 64% and 72% yields,
respectively. These results along with the satisfactory result
from N-benzyl-protected 11 (Table 1, entry 1) revealed that
benzyl related protecting groups are appropriate for this
coupling reaction.
1
2
3
4
5
6
Pd(OAc)2/1
Pd(OAc)2/2
Pd(OAc)2/BINAP
Pd(OAc)2/MOP
Pd(PPh3)4
77
29
44
48
-
Pd(OAc)2
49
To further test the scope and limitations of the reaction,
we examined a variety of substituted 2-bromobenzamides
(Table 3). Interestingly, this reaction depends on the elec-
a The reaction was conducted using a Pd catalyst (6.0 mol %), a ligand
(5.0 mol %), and Cs2CO3 (1.0 equiv) in dioxane for 24 h at 100 °C. bYields
of the isolated products.
Table 3. Effects of the Electronic Property of the Substituentsa
77% (Table 1, entry 1); however, ligand 2, BINAP, and MOP
did not show prominent effects (Table 1, entries 2-4), and
Pd(PPh3)4 completely inhibited the reaction (Table 1, entry
5). This coupling also proceeded under ligand-free conditions
(Table 1, entry 6). Hence, these results indicate that novel
phosphine 1 is a powerful ligand for this reaction.
As shown in Table 2, the outcome of the reaction strongly
depends on the amide substituents. The reaction of substrates
containing methyl, allyl, and phenyl substituents resulted in
low yields (Table 2, entries 1-3).5 However, substrates with
p-methoxy- and 2,4-dimethoxybenzyl moieties provided
entry
substrate
product
yield (%)b
1
2
3
4
5
6
7
8
15a: R1 ) R2 ) H, R3 ) NO2
15b: R1 ) NO2, R2 ) R3 ) H
15c: R1 ) R3 ) H, R2 ) F
15d: R1 ) Cl, R2 ) R3 ) H
15e: R1 ) R2 ) H, R3 ) Me
15f: R1 ) R3 ) H, R2 ) Me
15g: R1 ) OMe, R2 ) R3 ) H
15h: R1 ) R2 ) OMe, R3 ) H
16a
16b
16c
16d
16e
16f
-
-
45
37
81
67
41
92
(3) Phenanthridinone derivatives are often found in bioactive compounds
and have received much attention as valuable intermediates for nitrogen-
containing natural products. See: (a) Harayama, T.; Akamatsu, H.; Okamura,
K.; Miyagoe, T.; Akiyama, T.; Abe, H.; Takeuchi, Y. J. Chem. Soc. Perkin
Trans. 1 2001, 523-528. (b) Harayama, T.; Akiyama, T.; Nakano, Y.;
Shibaike, K.; Akamatsu, H.; Hori, A.; Abe, H.; Takeuchi, Y. Synthesis 2002,
237-241. (c) Bellocchi, D.; Macchiarulo, A.; Costantino, G.; Pellicciari,
R. Bioorg. Med. Chem. 2005, 13, 1151-1157. (d) Ishida, J.; Hattori, K.;
Yamamoto, H.; Iwashita, A.; Mihara, K.; Matsuoka, N. Bioorg. Med. Chem.
Lett. 2005, 15, 4221-4225.
16g
16h
9
59
(4) Typical procedure for a domino coupling: Pd(OAc)2 (2.5 mg, 0.010
mmol) was added to a solution of ligand 1 (3.6 mg, 0.0086 mmol) in 1,4-
dioxane (1.2 mL) under an argon atmosphere. After sonicating the solution,
11 (50 mg, 0.17 mmol) and Cs2CO3 (56 mg, 0.17 mmol) were added to the
solution at room temperature and the mixture was stirred for 24 h at 100 °C.
After stirring, H2O was added and then extracted with AcOEt. The organic
layer was washed with H2O and brine, dried over MgSO4, and evaporated.
The residue was purified by column chromatography on silica gel (hexane/
AcOEt, 7:3) to afford 12 (19 mg, 77%) as a colorless solid. The structure
of 12 was unambiguously determined by X-ray analysis. (See Supporting
Information.)
a The same conditions as those in Table 2 were used. bYields of the
isolated products.
tronic nature of the aromatic ring. The reaction with aryl
halides 15a-d, which possess electron-withdrawing groups,
did not proceed smoothly (Table 3, entries 1-4). On the
(5) The reaction did not proceed unless the amide nitrogen group was
protected. Only the starting material was recovered. The same observation
is depicted in ref 6.
184
Org. Lett., Vol. 9, No. 2, 2007

other hand, substrates 15e and 15f, which possess electron-
donating methyl substituents, afforded the coupling products
in 81% and 67% yield, respectively. It is noteworthy that
the reaction of 15h, which possesses an electron-rich phenyl
moiety due to electron donation from two methoxy groups,
afforded 16h in excellent yield (Table 3, entry 8). These
results clearly demonstrate that an electron-rich aryl moiety
makes the domino reaction efficient.
reactivities (Table 3, entries 4 and 7). However, the reaction
gave a mixture of all the theoretically predicted coupling
products, including homocoupled products 16d (25%) and
16g (26%) and cross-coupled 19 (14%) and 20 (6%) (Scheme
3A).10
Scheme 3. Extension of the Cross-Coupling Reaction
Another promising property of this coupling is the
compatibility with sterically hindered 3-substituted bro-
mobenzamides such as 15e (Table 3, entry 5). An extension
of this observation is demonstrated in the coupling of
naphthyl derivative 15i to binaphthyl 16i (Table 3, entry 9).
Because products 16e and 16i are axially chiral, further
applications of this protocol on asymmetric synthesis should
provide optically active compounds.
During the course of our investigation, Ferraccioli and
Catellani reported the same type of coupling reactions using
a different catalytic system.6,7 Taking both their proposed
mechanism and our results into account, the reaction possibly
proceeds through domino C-C and C-N bond formations
involving an ipso substitution as shown in Scheme 2. The
Scheme 2. Outline of the Catalytic Cycle
1
[a] The yields were calculated by H NMR.
Another coupling reaction with 15d and 21, which have
different N-protecting groups, also gave a mixture of
coupling products (Scheme 3B).11 Although selective cross-
coupling would be difficult, the convenience of this protocol
should be applicable to combinatorial chemistry as well as
to diversity oriented synthesis. Furthermore, the removal of
the PMB group proceeded under acidic conditions to give
24 as shown in Scheme 4. Therefore, various compounds,
which are diversified at the amide substituent, should be
readily prepared by the deprotection-alkylation sequence
at the resulting amide nitrogen group.
In summary, we have clarified that our ligand 1 works
well toward the C-C and C-N bond forming domino
reaction and have developed an efficient method for phenan-
thridinone synthesis. This reaction is a promising method
high reactivity of substrates with electron-donating substit-
uents on the aromatic ring (Table 3, entries 5-8) could
support a nucleophilic attack of the aromatic electron to Pd-
(II) (step A). After the deamidation reaction by the elimina-
8
tion of amine and CO2 or the isocyanate derivative9 to 18,
(9) During the reaction of 11 to 12 (Table 1, entry 1), we observed a
peak that corresponds to benzyl isocyanate (m/z 313) using GC-MS analysis.
For details of the GC-MS analysis, see Supporting Information. Moreover,
symmetrical urea derivative 25 was isolated in 40% yield from the
experiment of entry 4 in Table 2. Urea 25 could be derived from the
dimerization and subsequent decarboxylation of corresponding isocyanate
derivative 26.
the C-N bond is formed by the reductive elimination of
Pd(II) to yield phenanthridinone derivative 10.
Next, we expanded this coupling reaction to the cross-
coupling process. To examine the feasibility of this approach,
we conducted the reaction using an equimolar amount of
substrates 15d and 15g, which have nearly the same
(6) Ferraccioli, R.; Carenzi, D.; Motti, E.; Catellani, M. J. Am. Chem.
Soc. 2006, 128, 722-723.
(7) A similar reaction was originally discovered by Caddick et al. during
their investigations of an intramolecular Heck reaction of 13b in the presence
of an N-heterocyclic carbene (NHC) ligand. Phenanthridinone 14b was
obtained in 32% yield. See: Caddick, S.; Kofie, W. Tetrahedron Lett. 2002,
43, 9347-9350.
(8) Ref 6 has proposed a mechanism for the decomposition of the amide
substituent by a nucleophilic attack of the palladium-bonded bicarbonate
anion to yield an amine derivative and CO2.
(10) The reason for the predominant yield of homocoupling products
16d and 16g might be explained by the reactivity order of the substrates.
(11) The predominant formation of N-benzyl-substituted phenanthridinone
derivative 16d could be explained by the high reactivity of N-benzyl-
protected substrate 15d.
Org. Lett., Vol. 9, No. 2, 2007
185

(The University of Tokyo) for their valuable discussions on
the mechanistic consideration of the reaction. Financial
support from the Uehara Memorial Foundation is also
gratefully acknowledged.
Scheme 4. Deprotection of the PMB Protecting Group
Supporting Information Available: Spectral data for all
new compounds and details for experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
for developing a variety of phenanthridinone derivatives and
should be applicable to a broad range of substrates.12
Further mechanistic studies and applications to prepare
axially chiral biaryls as well as to develop alternative
bioactive heterocycles using this catalytic system are cur-
rently underway.
OL062599Z
(12) The reaction with N-tethered 2-bromobenzamide 27 gave phenan-
thridinone dimer 28 as the major product. For the details of this reaction,
see Supporting Information.
Acknowledgment. We thank Prof. Yasuhiro Uozumi
(Institute for Molecular Science) and Prof. Kyoko Nozaki
186
Org. Lett., Vol. 9, No. 2, 2007